Neonatal-onset Multisystem Inflammatory Disease

NORD gratefully acknowledges Dr. Hal Hoffman, Associate Professor of Pediatrics and Medicine, Division of Rheumatology, Allergy, and Immunology at the University of California at San Diego School of Medicine, for assistance in the preparation of this report.

Synonyms of Neonatal-onset Multisystem Inflammatory Disease

chronic, infantile, neurological, cutaneous and articular syndrome

CINCA

NOMID

General Discussion

Neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous articular (CINCA) syndrome, is a rare, congenital, systemic, inflammatory condition distinguished by fever, rash, joint disease, and central nervous system (CNS) disease. The hallmark of NOMID is onset during infancy or early childhood.
NOMID is the most severe form of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene. These syndromes are characterized by fever, rash, and joint pain.

Signs & Symptoms

In addition to fever, symptoms of NOMID involve the skin, CNS and joints. Skin rashes occur in all patients within the first six weeks of life and persist throughout their lives. CNS symptoms include chronic meningitis, mental retardation, seizures and sensory organ dysfunction, which results in vision and hearing loss. Joint inflammation and joint and bone deformities range in severity. Enlargement of the knee-cap is also characteristic of NOMID.

Other symptoms include stunted growth, enlargement of the liver and spleen, an abnormal increase in the number of white blood cells, an elevation in levels of the protein amyloid A and C-reactive protein in the blood and an increase in the erythrocyte sedimentation rate (blood tests used to measure elevations of these markers can detect or grade inflammation). In addition, abnormal facial features can sometimes be seen.

NOMID shares symptoms, and should not be confused, with juvenile idiopathic arthritis (JIA). High recurrent fevers, joint pain, deforming joint disease and rash are symptoms of both NOMID and JIA. However, NOMID is differentiated by the onset of skin disease at birth and a persistent rash. In addition, many patients with NOMID have nonspecific joint pain and enlargement of the knee-cap, while patients with JIA present with inflamed synovial joints, such as the shoulder or knee, increased production of fluid in the synovial joints and warm, swollen, stiff joints.

NOMID patients suffer from frequent, almost daily flare-up episodes which cause great discomfort, can be very debilitating, and may require medical assistance during the episodes. Some patients are unable to walk or bear weight on their legs due to joint damage and/or pain. The majority of children with NOMID have cognitive and mental deficits and/or learning disabilities as well as vision and hearing loss. There is a 20 percent mortality rate before adulthood associated with NOMID.

Causes

About 50-60 percent of those who are diagnosed with NOMID have heterozygous mutations in the CIAS1/NLRP3 gene that codes for the protein cryopyrin (NALP3). Mutations in this gene are hypothesized to cause increased activity of a protein complex containing cryopyrin. This protein complex is known as the inflammasome and regulates inflammation in the body. Increased inflammasome activity results in increased release of a protein known as interleukin (IL) 1ß, which leads to symptoms of inflammation such as fever and joint pain.

NOMID appears to follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Affected Populations

Since NOMID is a newly discovered condition, the actual incidence and prevalence of the disease is difficult to determine.

Related Disorders

Symptoms of the following disorders can be similar to those of NOMID, and there is significant phenotypic overlap. Comparisons may be useful for a differential diagnosis.

Familial cold autoinflammatory syndrome (FCAS), also known as familial cold urticaria, is a rare, inherited inflammatory disorder characterized by intermittent episodes of rash, fever, joint pain and other signs/symptoms of systemic inflammation triggered by exposure to cold. Onset of FCAS presents during infancy and early childhood and persists throughout the patient’s life. FCAS is one of the cryopyrin associated periodic syndromes (CAPS) caused by mutations in the CIAS1/NLRP3 gene.

Muckle-Wells syndrome (MWS) is one of the cryopyrin associated periodic syndromes (CAPS). Individuals with MWS often have episodic fever, chills, and painful joints. Sometimes these symptoms are exacerbated by cold similar to the related condition FCAS, but can also be triggered by other stimuli or unprecipitated. In most cases, MWS patients develop progressive hearing loss. In some MWS cases amyloidosis develops later in life, a disease in which an abnormal accumulation of the protein amyloid occurs in a patient’s tissues and organs. Accumulation of amyloid in the kidneys results in damage and often kidney failure if untreated.

Diagnosis

Diagnosis of NOMID is determined through an evaluation of a patient’s symptoms and medical history. Confirmation of the diagnosis is achieved through genetic testing although almost half of all NOMID patients do not possess a mutation in the CIAS1/NLRP3 gene.

Standard Therapies

Treatment

Therapies that suppress inflammation, including high-dose corticosteroids and disease-modifying antirheumatic drugs have been used to treat NOMID. These treatments tend to be only moderately effective, however, with inflammation persisting in most children.

There are no therapies that are FDA approved for the treatment of NOMID. However, there is significant clinical experience in NOMID with IL-1 targeted therapies.

Kineret (Anakinra) by Biovitrum pharmaceuticals, an IL-1 receptor antagonist, has been used extensively in NOMID patients with excellent clinical results, although higher than standard doses are often required. However, it is not currently approved by the FDA for the treatment of NOMID or any of the CAPS diseases at this time.

Ilaris (Canakinumab) by Novartis Pharmaceuticals, a monoclonal antibody to interleukin-1 beta, was approved by the FDA in 2009 as a treatment for children and adults with CAPS, including familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). Ilaris has been used to successfully treat NOMID patients and is approved in Europe, although higher than standard doses are often required and it is not FDA approved for NOMID at this time.

Arcalyst (Rilonacept) by Regeneron Pharmaceuticals, an interleukin-1 blocker, was approved by the FDA in 2008 for the treatment of CAPS, including FCAS and MWS, in adults and children 12 and older, but it is not approved in NOMID and there is no clinical experience in NOMID patients.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

Contact for additional information about NOMID:

Dr. Harold M. Hoffman

Associate Professor of Pediatrics and Medicine

Division of Rheumatology, Allergy, and Immunology

University of California at San Diego School of Medicine

(858) 534-2108

hahoffman@ucsd.edu

Resources

RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.

Years Published

2007, 2011

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